Keio University Reveals Gut's Role in Priming T Cells for Multiple Sclerosis Neuroinflammation

Keio University's Breakthrough on the Gut-Brain Axis in Multiple Sclerosis

Recent research from Keio University has illuminated a critical connection in the gut-brain axis for multiple sclerosis (MS), a chronic autoimmune disease affecting the central nervous system (CNS). In a study published on March 27, 2026, in Science Immunology, scientists revealed how intestinal epithelial cells (IECs) in the gut 'prime' pathogenic T helper 17 (Th17) cells, which then migrate to the brain and spinal cord, fueling neuroinflammation. This discovery positions the gut as a key player in MS pathogenesis, offering fresh avenues for therapy beyond traditional B-cell targeting.

Multiple sclerosis impacts approximately 2.8 million people worldwide, with prevalence rising in Japan from 7.6 to 11.5 per 100,000 between 1990 and 2021. While MS was once rare in Japan, environmental and lifestyle shifts, including Western diets, may contribute to this trend. Keio researchers, led by Assistant Professor Shohei Suzuki and Associate Professor Tomohisa Sujino from the Division of Gastroenterology and Hepatology at Keio University School of Medicine, used advanced models to uncover this mechanism.

Understanding Multiple Sclerosis and the Emerging Gut-Brain Connection

MS occurs when the immune system mistakenly attacks myelin, the protective sheath around nerve fibers, leading to symptoms like fatigue, vision loss, and mobility issues. The exact triggers remain elusive, but genetic, environmental, and microbial factors interplay. The gut-brain axis—the bidirectional communication between the gastrointestinal tract and CNS via neural, hormonal, and immune pathways—has gained attention. Dysbiosis, or imbalance in gut microbiota, correlates with MS flares, as seen in earlier Keio studies from 2015 showing altered microbiomes in Japanese MS patients.

In MS, pro-inflammatory cytokines and immune cells cross barriers, exacerbating CNS damage. Th17 cells, characterized by interleukin-17 (IL-17) production, drive inflammation. Prior research linked gut bacteria to Th17 differentiation, but cellular mechanisms were unclear until now.

Keio's Innovative Methodology: From Mouse Models to Human Biopsies

The team employed the experimental autoimmune encephalomyelitis (EAE) mouse model, mimicking MS neuroinflammation. Single-cell RNA sequencing of intestinal biopsies revealed Th17 accumulation in the ileum—the small intestine's final segment rich in Peyer's patches for immune sampling.

Key techniques included:

• Conditional MHC class II (MHC II) deletion in IECs to test antigen presentation's role.
• Co-culture assays with IEC organoids and myelin oligodendrocyte glycoprotein (MOG) antigen, showing MHC II-dependent Th17 polarization.
• Kaede transgenic mice for photoconversion tracking: violet light turns gut Th17 cells fluorescent red, confirming migration to spinal cord.
• Human validation via ileal biopsies from MS patients versus controls, mirroring mouse IEC MHC II upregulation.

These rigorous methods bridged preclinical and clinical data, highlighting IECs' unusual MHC II expression—typically limited to professional antigen-presenting cells like dendritic cells.

Core Findings: IECs as Unlikely Antigen Presenters

Central discovery: IECs upregulate MHC II during MS/EAE, presenting gut antigens (possibly commensal-derived) to CD4+ T cells, priming them into pathogenic Th17 cells expressing RORγt transcription factor. These cells traffic via circulation to CNS, producing IL-17 and interferon-gamma, worsening demyelination.

Deleting IEC MHC II slashed Th17 numbers and EAE severity. Photoconversion proved gut lamina propria Th17 cells directly contribute to CNS infiltrates. Human MS biopsies confirmed elevated IEC MHC II and Th17 signatures, conserved across species.

"The gut microbiota influences neurological diseases like MS, but linking microbes to brain inflammation was unclear," noted Dr. Sujino. Dr. Suzuki added, "Modulating IEC antigen presentation offers novel MS treatments." Read the full study in Science Immunology.

Photo by Jonathan Gong on Unsplash

Human Relevance and Japanese MS Context

Japan's MS prevalence, though low at ~15-22 per 100,000 regionally, is climbing, per Global Burden of Disease data. Northern Japan reports 22.4/100,000 crude prevalence in 2021, with optic-spinal forms common. Keio's findings align with prior Japanese research, like 2015 gut dysbiosis studies, suggesting diet-microbiome shifts fuel rises.

Biopsies from Japanese MS patients showed ileal IEC MHC II spikes, implying universal mechanisms despite lower incidence. This underscores environmental modulators like microbiota in low-prevalence areas.

Therapeutic Horizons: Targeting the Gut for MS Relief

Current MS drugs like ocrelizumab deplete B cells, but Th17 focus shifts to T cells. Gut modulation—fecal transplants, diets boosting anti-inflammatory microbes, or IEC MHC II inhibitors—holds promise. Blocking IEC presentation could prevent Th17 priming without broad immunosuppression.

Related Keio work, like January 2026 PNAS on M cells priming γδT17 cells, complements this, suggesting multi-layered gut interventions. Clinical trials targeting gut-brain axis are nascent globally, but Japan's precision medicine push positions Keio ideally. Medical Xpress coverage details potentials.

Keio University: A Hub for Immunology and Neuroscience

Keio University School of Medicine, Tokyo, excels in translational research. The Division of Gastroenterology and Hepatology integrates microbiome studies with neurology, leveraging Japan's advanced single-cell tech. Keio's Bio2Q center explores human biology-microbiome-quantum interfaces, funding this via JSPS grants.

Sujino and Suzuki's team builds on Keio's legacy, including early MS epidemiology surveys showing rising trends. This positions Keio as leader in Asian MS research, fostering collaborations like with Miyarisan Pharmaceuticals.

Broader Landscape: Global and Japanese Gut-MS Research

Worldwide, Casetta et al. (2017) linked MS microbiomes to Th17 exacerbation in mice. Japanese studies, e.g., Miyake (2023) on northern prevalence, note 50% rise. Keio's IEC focus advances beyond dysbiosis, pinpointing IEC-MHC II-Th17 axis.

Challenges: Japan's aging population amplifies MS disability-adjusted life years (DALYs). Solutions include microbiota profiling for risk prediction, per Luxembourg studies adaptable to Japan.

Photo by Daniel Bernard on Unsplash

Challenges, Impacts, and Future Outlook

Translating to humans requires IEC-targeted drugs, mindful of gut barrier integrity. Impacts: earlier intervention could slow Japan's MS rise, reducing ~59% female-predominant DALYs.

Future: Keio plans IEC modulators; global trials test fecal microbiota transplants. Actionable: MS patients consider anti-inflammatory diets (Mediterranean, high-fiber) supporting beneficial microbes. Neuroscience News elaborates on migration tracking.

This Keio breakthrough redefines MS as gut-orchestrated, promising precision therapies from Japanese innovation.